Sustained release pharmaceutical tablets



p 1960 J. v. SWINTOSKY 2,951,792

SUSTAINED RELEASE PHARMACEUTICAL TABLETS Original Filed Aug. 16, 1954 a 4 l2 f I I2 2 i\ |6 n; L L L l4 IO 6 Fl 6. I

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INVENTOR.

JOSEPH V. SWlNTOSKY BYBW ATTORNEYS United States Patent SUSTAJNED RELEASE PHARMACEUTICAL TABLETS Joseph V. Swintosky, Perkiomenville, Pa., assignor to Smith Kline & French Laboratories, Philadelphia, Pa., a corporation of Pennsylvania Continuation of application Ser. No. 449,880, Aug. 16, 1954. This application Nov. 18, 1959, Ser. No. 853,844

Claims. (Cl. 167-82) This invention relates to a pharmaceutical tablet and to such a tablet which provides an immediately released dosage to achieve a therapeutic level and a sustained release dosage to maintain a therapeutic level of the medicament over an extended period of time. The tablet of this invention provides a substantially constant uniform release of medicament over an extended period of time even as the surface areas of the sustained release portion wear away.

In order to achieve efficient results from a very large number of drugs, it has been found advantageous to provide a uniform sustained release of such drugs over an extended period of time. The problem is further complicated in that it has been found in such cases that an initial immediately released dosage is usually necessary to bring the medicament up to the desired therapeutic level promptly in conjunction with means for gradually releasing uniform amounts of the medicament to sustain .the therapeutic level.

The best known solution of this uniform sustained release problem has been the use of large numbers of small pellets contained in a capsule, a percentage of the pellets providing an initial dosage of a medicament to promptly achieve the desired therapeutic level and the remaining percentage being variously coated with time delay material to provide gradual release of the medicament to sustain the therapeutic level. Although providing a thoroughly acceptable product from the point of view of its efficacy, this sustained release product is very difficult to make and, further, is of necessity an expensive product not easily adaptable to mass production techniques.

Now in accordance with this invention there is provided a tablet which provides an initial dosage to promptly achieve a therapeutic level together with excellent substantially uniform sustained release of the medicament to sustain the therapeutic level over a period of in excess of four hours and up to twelve hours. The tablet is advantageous in that it is easy to make and lends itself to mass production through the use of a tableting machine. Further, the production of the tablet is markedly less expensive than the production of the above discussed encapsulated pellets.

The tablet in accordance with this invention comprises a substantially flat faced tablet having a layer of medicament dispersed in a conventional filler such as, for example, terra alb a, milk of sugar, talc or stearic acid. This layer, on reaching the gastro-intestinal tract is quickly dissolved or distintegrated in the body fluids and thus rapidly provides a therapeutic blood level of the medicament.

Contiguous with the first immediately released layer is a sustained release layer containing the same medicament dispersed in time delay material.

The total surface area of the sustained release layer, including the side surface area and the surface area abutting the immediately released layer, will be from 2.5 to

.25 times the side surface area of the sustained release layer. A sustained release layer made in accordance with these limitations provides a substantially constant uniform release of medicament as against, for example, a similar composition in the form of a ball which would, as the surface area were away, provide an ever decreasing amount of medicament for a unit of time.

More specifically, the immediately released layer may be conventionally formed by mixing the medicament with one or more fillers and granulating, using, for example, water, an acacia solution, starch paste or a gelatin solution and a screen of, for example, 8 to 30 mesh. The thus formed granules are dried and then compressed into substantially fiat faced tablets.

The sustained release layer may also be prepared using the granulation technique. The medicament may, for example, be dispersed in a melt of a suitable time delay material and the mix congealed. The congealed mix may then be passed through a screen of, for example, 8 to 30 mesh. If an increased release rate is desired, the granulation can be mixed with a small amount of hydrophilic material.

The immediately released layer in tablet form is then placed in a tablet machine die and the granulation for the sustained release layer is added to the die and compressed by the tablet machine punch on to the tablet to form a contiguous two layer tablet.

Alternatively, the granulation for the immediately released layer and the granulation for the sustained release layer may be added to the die of a tableting machine one on top of the other and then compressed by the tablet machine punch.

The hydrophilic material for the immediate release layer, if desired, may be, for example, starch, sugar, alginic acid or colloidal magnesium aluminum silicate.

The time delay material for the sustained release layer will be a solid lipid material such as, for example, an alcohol or ester, alone, or an admixture thereof. The fatty alcohols may have from 12 to 31 carbon atoms and may be, for example, lauryl alcohol, cetyl, stearyl, myristyl, myricyl, arachyl, carnubyl or ceryl alcohol.

The esters may be mono, dior triglyceryl esters formed from fatty acids having from 10 to 22 carbon atoms, such as, for example, glyceryl distearate, glyceryl tristearate, glyceryl monostearate, glyceryl dipalmitate, glyceryl tripalmitate, glyceryl monopalmitate, glyceryl dilaurate, glyceryl trilaurate, glyceryl monolaurate, glyceryl didocosanoate, glyceryl tridocosanoate, glyceryl monodocosanoate, glyceryl monocaprate, glyceryl dicaprate, glyceryl tricaprate, glyceryl monomyristate, glyceryl dimyristate, glyceryl trimyristate, glyceryl monodecenoate, glyceryl didecenoate or glyceryl tridecenoate, hydrogenated castor oil, hydrogenated peanut oil and hydrogenated coconut oil.

Further exemplary of esters are esters of a fatty acid having from 12 to 31 carbon atoms and a fatty alcohol having from 12 to 31 carbon atoms, the ester having a carbon atom content of from 24 to 62, or a mixture thereof. Exemplary are myricyl palmitate, beeswax, cetyl palmitate, spermacetic wax, myricyl cerotate, carnauba wax, cetyl myristate, ceryl palmitate, ceryl cerotate, myricyl melissate, stearyl palmitate, stearyl myristate, lauryl laurate.

The invention will be further clarified by a study of the following description in conjunction with the drawing, in which:

Figure 1 is a vertical section of a tablet in accordance with this invention.

Figure 2 is an alternate embodiment of a tablet in accordance with this invention.

As shown in Figure 1, a cylindrical tablet 2 has a sustained release layer 4 and an immediate release layer 6. Sustained release'layer '4 has faces 8 and 10 and a side 12. Immediate release layer 6 has a face 14 and a side 16. The total surface area of sustained release layer 4, including side 12, is about 9 times the surface areaof side 12.

In Figure 2 an alternative tablet 20 is disclosed. Tablet 20- has a sustained release layer 22, an upper immediate release layer 24 and a lower immediate release layer 26. Sustained release layer 22 has an upper face 28, a lower face 30 and a side 32. Immediate release layer 24 has a face 34 and a side 36. Immediate release layer 26 has a'face 38 and a side 40. In the case of tablet 20, the surface area of sustained release layer 22 is about times the surface area of the sides of this layer.

The tablet in accordance with this invention and a method for its preparation will be further illustrated by the following specific example:

Example A granulation is prepared from the following powders:

Gm. Stearic acid 16.0 Talc 16.0 Aminophylline 64.0

The powders are mixed well in the dry condition. Then cc. of gelatin in distilled water is added slowly, with mixing, to the powders. The wet mixture is then passed through a No. 10 screen and dried overnight at 110 F. The dried granules are then passed through a No. 14 screen. These dried granules are compressed into /z-inch cylindrical flat faced tablets, each weighing 1% grains and designated tablets (X).

Another granulation is prepared by melting 300 gms. hydrogenated castor oil and adding to this 300 gms. aminophylline. Thisproduct is mixed Well until congealed. The congealed product is put through a comminution mill utilizing a No. 10 screen. Then 65 gms. of this granulation are mixed with 5 gms. of starch and designated granulation (Y).

The final sustained drug release tablet is prepared from tablets (X) and granulation (Y) as follows:

A tablet (X) isplaced in the /2 inch die. 7.0 grains of granulation (Y) are added to the die and compressed onto tablet (X) using a fiat head punch. The final tablet provides uniform sustained release for about 8 hours and is useful in treating, for example, asthmatic conditions, congestive heart failure and in general where aminophylline has been used heretofore.

Although the invention is specifically exemplified using aminophylline, it will be appreciated that it is useful with any medicament which it is desired to provide in sustained release form. Thus, for example, the medicament may be a sympathomimetic amine such as dextroamphetamine sulfate; a sedative-hypnotic such as, for example, a barbiturate such as phenobarbital or amobarbital; an antihistaminic such as, for example, chlorprophenpyridarnine maleate or thenylpyramine hydrochloride; an antispasmodic such as, for example, homatropine methylbromide, hyoscyamine sulfate, atropine sulfate or scopolamine hydrobromide.

This is a continuing application based on my copending patent application, Serial No. 449,880, filed August 16, 1954, now abandoned.

What is claimed is:

1. A substantially flat faced sustained release pharmaceutical tablet having an immediate release layer containing a medicament dispersed in a filler, said immediate release layer providing a therapeutic blood level of said .medicament, a sustained release layer contiguous with sustained release layer including the face abutting the immediate release layer being in the range of from 2.5 to 25 times the side surface area of said sustained release layer, said sustained release layer providing a substantially uniform release for a period of in excess of four hours, said immediate release layer being exterior of said sustained release layer.

2. A substantially flat faced sustained release pharmaceutical tablet having an immediate release layer'c'ont aining a medicament dispersed in a filler, said immediate release layer providing a therapeutic blood level of said medicament, a sustained release layer containing the same medicament dispersed within granules of a solid ingestible lipid time delay material selected from the group consisting of fatty alcohols having from 12 to 31 carbon atoms, glyceryl esters formed from fatty acids having from 10 to 22 carbon atoms and esters having from 24 to 62 carbon atoms formed from fatty acids having from 12 to 31 carbon atoms and fatty alcohols having from 12 to 31 carbon atoms, said granules being in admixture with a solid ingestible hydrophilic material, said sustained release layer being contiguous with said first mentioned layer, the total surface area of said sustained release layer including the face abutting the immediate release layer being in the range of from 2.5 to 25 times the side surface area of said sustained release layer and said sustained release layer providing a substantially uniform release for a period of in excess of four hours, said immediate release layer being exterior of said sustained release layer.

3. A substantially flat faced sustained release pharmaceutical tablet having an exposed immediate release portion containing a medicament dispersed in a filler, said immediate release portion providing a therapeutic level of said medicament, a sustained release portion containing the same medicament dispersed within granules of a solid ingestible lipid time delay material selected from the group consisting of fatty alcohols having from 12 to 31 carbon atoms, glyceryl esters formed from fatty acids having from 10 to 22 carbon atoms and esters having from 24 to 62 carbon atoms formed from fatty acids having from 12 to 31 carbon atoms and fatty alcohols having from 12 to 31 carbon atoms, the total surface area of said sustained release portion being in the range of from 2.5 to 25 times the side surface area of said sustained release portion, said sustained release portion providing a substantially uniform release of the medicament for a period of in excess of four hours, said immediate release portion being exterior of said sustained release portion.

4. A substantially flat faced sustained release pharmaceutical tablet having a single immediate release layer containing a medicament dispersed in a filler, said immediate release layer providing a therapeutic blood level of said medicament, a single sustained release layer contiguous with said first mentioned layer and containing the same medicament dispersed within granules of a solid ingestible lipid time delay-material selected from the group consisting of fatty alcohols having from 12 to 31 carbon atoms, glyceryl esters formed from fatty acids having from 10 to 22 carbon atoms and esters having from 24 to 62 carbon atoms formed from fatty acids having from 12 to 31 carbon atoms and fatty alcohols having from 12 to 31 carbon atoms, the total surface area of said sustainedrelease layer including the face abutting the immediate release layer being in the range of from 2.5 to 25 times the side surface area of said sustained release layer, said sustained release layer providing a substantially uniform release for a period of in excess of four 5 hours, said immediate release layer being exterior of said sustained release layer.

5. A substantially flat faced sustained release pharmaceutical tablet having a pair of immediate release layers each containing a medicament dipsersed in a filler, said immediate release layers providing a therapeutic blood level of said medicament, a sustained release layer between said immediate release layers and containing the same medicament dispersed within granules of a solid ingestible lipid time delay material selected from the group consisting of fatty alcohols having from 12 to 31 carbon atoms, glyceryl esters formed from fatty acids having from 10 to 22 carbon atoms and esters having from 24 to 62 carbon atoms formed from fatty acids having from 12 to 31 carbon atoms and fatty alcohols having from 12 to 31 carbon atoms, the total surface area of said sustained release layer including the faces abutting the immediate release layers being in the range of from 2.5 to 25 times the side surface area of said sustained release layer, said sustained release layer providing a substantially uniform release for a period of in excess of four hours, said immediate release layers being exterior of said sustained release layer.

Whyte June 3, 1902 Svedres May 28, 1957 

1. A SUBSTANTIALLY FLAT FACED SUSTAINED RELEASE PHARMACEUTICAL TABLET HAVING AN IMMEDIATE RELEASE LAYER CONTAINING A MEDICAMENT DISPERSED IN A FILLER, SAID IMMEDIATE RELEASE LAYER PROVIDING A THERAPEUTIC BLOOD LEVEL OF SAID MEDICAMENT, A SUSTAINED RELEASE LAYER CONTIGUOUS WITH SAID FIRST MENTIONED LAYER AND CONTAINING AND SAME MEDICAMENT DISPERSED WITHIN GRANULES OF A SOLID INGESTIBLE LIPID TIME DELAY MATERIAL SELECTED FROM THE GROUP CONSISTING OF FATTY ALCOHOLS HAVING FROM 12 TO 31 CARBON ATOMS, GLYCERYL ESTERS FORMED FROM FATTY ACIDS HAVING FROM 10 TO 22 CARBON ATOMS AND ESTERS HAVING FROM 24 TO 62 CARBON ATOMS FORMED FROM FATTY ACIDS HAVING FROM 12 TO 31 CARBON ATOMS AND FATTY ALCOHOLS HAVING FROM 12 TO 31 CARBON ATOMS, THE TOTAL SURFACE AREA OF SAID SUSTAINED RELEASE LAYER INCLUDING THE FACE ABUTTING THE IMMEDIATE RELEASE LAYER BEING IN THE RANGE OF FROM 2.5 TO 25 TIMES THE SIDE SURFACE AREA OF SAID SUSTAINED RELEASE LAYER, SAID SUSTAINED RELEASE LAYER PROVIDING A SUBSTANTIALLY UNIFORM RELEASE FOR A PERIOD OF IN EXCESS OF FOUR HOURS, SAID IMMEDIATE RELEASE LAYER BEING EXTERIOR OF SAID SUSTAINED RELEASE LAYER. 